Process of separation of higher molecular weight dicarboxylic acids



y 1956 TAKERU HIGUCHI I 2,744,057

PROCESS OF SEPARATION OF HIGHER MOLECULAR WEIGHT DICARBOXYLIC ACIDS Filed Sept. 6, 1951 4 Sheets-Sheet 1 SOLUTION OF DICARBOXYLIC I ACIDS; THEN ELUANT FILTER PAPER BE'D OF SILICIC ACID WITH ADHERENT AQUEOUS PHASE; ORGANIC PHASE IN INTERSTICES FIG. I

GLASS WOOL INVENTOR. ELUATE I TAKERU HIGUCHI ATTORNEY y 1, 1956 TAKERU HIGUCHI 2,744,067

PROCESS OF SEPARATION OF HIGHER MOLECULAR WEIGHT DICARBOXYLIC ACIDS 4 Sheets-Sheet 2 Filed Sept. 6, 1951 NOLLOVHd 83d SSVS 'GLS :IO "1W INVENTOR.

TAKERU HIGUCHI BY g? 64% ATTORNEY y 1956 TAKERU HlGUCHl 2,744,@67

PROCESS OF SEPARATION OF HIGHER MOLECULAR WEIGHT DICARBOXYLIC ACIDS 4 Sheets-Sheet 3 Filed Sept. 6, 1951 NOILOVHJ 83d asva ms =10 "m INVENTOR- TAKERU HIGUCHI ATTORNEY y 1, 1956 TAKERU HlGUCHl 2,744,067

PROCESS OF SEPARATION OF HIGHER MOLECULAR WEIGHT DICARBOXYLIC ACIDS Filed Sept. 6, 1951 4 Sheets-Sheet 4 TAKERU HIGUCHI flaw ATTORINYEIY United States Patent 2,744g067 success or sEPARATIoNtiFfHmHEnMonten- LAR WEIGHT DICARBOXYLIC ACIDS Taker-u mg ehi, Madison, Wis, fa'ss ignor to The C. P.

'Hall Company "of Illinois, Chicago, "111., a corporation Application September 6, 1951, Serial NofZflSQiUS s Clairns. or. 210- 425 jTliis iiiven 'tiob relates to the separation of higher "molecular FWeigh't straight 'chain"dicaibbxylic acids from title another. "By higher molecular Weight 'dicarboxylic acids, we refer to dic'fboxylic *aci'd's 'eoii't'a'ining six or more carbon atoms. This invention relates more particularly to the separation of acids, having chains of six to ten carbo'n'atom's.

DEFINITIONS The *aqueous phase of the system refers to t heaque ous solution adsorbed 'on the adsorbent. v V

The organic phase is the non-aqueous or external phase of the system. If the dicarboxylic acids are added to the system in solution (and this is not-necessar in a'cont'inuous process) the solvent employed 'vvill become part of the organic phase.

Partition coefficient is concentration in water concert-timbre organic phase When-the two phases are in equilibrium. 4

iDevelopment? refers to the process of increasing separation achieved by diflerential elution of the component acids.

THE rkoeess I fine-process er this invention employs a se entasolub'le "hydrop'hilic adsorbent earne which holds "the aqueous phase of the system. The bed is usually stationary. If a moving bed is employed, as 1'1- b er with a .pH above 4.5, mesdl and thi'snialges it possible to use organ c 'phase iv ich is more polar than co n16 be dwithoiit the Hfifier. The indie polah'so'lvents aref'd'e' H d because they are Bene sblve'nt's' flier the jdicarb ar sen. For menboxy-lie aeizrs with a 'chain team "at sig ts te earson latdtfis a pH of 5.1 to 6 is piefcri e d. btifier may be 1 molar orZ molar, etc. a; desired. High-molar bufrefs read a, salt m n the acids but basses; higher Barter capacity. The butter maintains the pH of the aqueous phase substantially constant throughout the process. Without 'sufficien'tly high buffer "concentration, the acid- -ity of the aqueous phase increases as the dicarboxylic a amant/651mm it thus decreasing the effective partitionboeificients of the respective acids and decreasing the eificienc'y of -the separation. Butters which may be enemy include "citrate, amage, phosphate pyroplfosphat'e, and other chemicals which give the desired hy- I Patented"May --l, 1956 drogen ion concentration and 'a're soluble in the aciuebus phase and substantially insoluble in the 'org'aiii'cphas'e so that they Will not readily leach outof the aqueous phase into the'brganic phase. The hydrogen 'ioncoticentration determines the 'rateat Whichthe respective dicarboirylic acids are "eluted in their travel "throughfthe adsorbent bed. The greater thehlkalinity, the slewer is'the rate 'ofelution, and vice versa. 'Bufler conciftrations up to 3 molarmay'be used.

The dicarboxylic acids are introduced into the "adsorbent bed in solution in a solvent which'i's substantially immiscible with theaqueousphaseaiidis'bf relatively low polarity. In a continuous process, organic 'ph'ase may be withdrawn from the system and usedas the-'stiL vent for the mixed dicarboxylic acids. Frbrn 'an analytical standpoint a solvent mixture containing essentially chloroform is preferied for supplying the dic'arbbxylic acids to the bed of hydrophilic material. Preferably more or less of 'a more'polarsolvent, "such as tertiary amyl alcohol or butanol, etc. is added "to the emeraform to increase its polarity, arid thus the solubility of the acids in the chloroform. Other solvents may be preferred commercially, 'such "as dichloroben'zene, 1,2,3- trichloropropane, 'be'nz'ene (with'addition 0t suflicient a1- cohol to increase its pola'rity), ethylene dichloride, "etc. Instead of the alcohols one might employ other highly polar solvents to "increase the solvency at the non-polar solvent, such as m'ethyl'ethyl "ketbne, diethyl ketone, methylpropyl ketone, e'tc. n

The 'eluant employed must be substantially immiscible with 'the Water "phase. Using a stationary 'adsorbefit bed, the removal of acids from the fixed aqueous'ph'ase may be facilitated 'by increasing the'polari't'yofthe enters as the process proceeds, eac'h increiiient being more polar than the preceding increment. Thus, as the i'ernov' or higher molecular Weight acids tjcc'urs, asolveiit con "iiiingin'crea'sing amounts of more p'oiarconstitti "s siichas the alcohols, 'etc. will 6rdiirarily be employed.

The higher molecular Weight straight-ch dietitboxyIio-acids which bray be se arated by this -ptoces's iiielude:

Due to the smaller partition coefficient of dic'arboxyl'ic 3Cid$ ;0f greater molecular Weight, suchas those containfing 12 carbon atoms and more, buifersolutions of higherpH arepreferred' where the separation ofsuch longerchainacids is involved. Theoretically 'an increase of 1.0 in the pH isfdesi-rable for-each increase of 4 carbon atoms in the chain length of the'dicarboxy'lic acid. Thus, in the separation of straightchain acids having 6 to l0 carbon atoms inthe, chain "a pH of 5.4 is satisfactory. The separation of acids of :6 'to 10 carbon atoms from acids o'f-greater chain length can also be accomplished with a buffer of this pH. However, forthe'separatioii of close homologues of higher than 610 chain length, a higher pH Will be desirable.

, In utilizing the'proc'ess'for the quantitative or qualitative'analysis of -a mixture of dicarboxylic acids, a temperature range near room temperature Will ordinarily be to a derivative, for example, by forming an insoluble salt, as by the addition of metallic hydroxide. Another method of separating the acids would be by treating the solution in a water-immiscible solvent with a water solution of ammonia to produce the ammonium salt. On separationof the acid from the solvent, the solvent may be used again as eluant with such adjustment of the polarity, etc. as may be required.

The invention will be further described by reference to the accompanying drawings, in which Fig. l is a schematic showing of apparatus which may be employed in the process; and

Figs. 2-4 are graphs which illustrate how effectively the process may be used. For analysis the apparatus will be regular laboratory equipment. For commercial operations, a column 2. foot in diameter up to several feet will be used, and the column will be up to five or ten or more feet in height.

For laboratory analysis a 20 mm. Pyrex column 45 cm. long may be used. The bed may be prepared as follows: grade) and 25 ml. of the aqueous phase are thoroughly worked together in a 400 ml. beaker with a spatula. Roughly 200 ml. of 3% n-butanol, 97% chloroform mixture are added and a homogeneous suspension formed by vigorous stirring. This suspension is packed incrementwise into the column, care being taken to prevent formation of air pockets or other forms of heterogeneity. Each increment is packed down uniformly, quite firmly with a close-fitting glass plunger. Finally a circle of filter paper is placed on the top of the packing.

The following examples illustrate the invention. In these examples the adsorbent bed was prepared as described above, and remained stationary, the feed solution of the dicarboxylic acids, and then the eluant were poured in onto the top of the filter paper covering the bed. In preparing the bed the aqueous phase was prepared with citrate buffer. Where one-molar buffer is mentioned in the examples the aqueous phase was prepared by adding sutficient one molar citric acid solution to one molar sodium citrate solution to give the desired hydrogen ion concentration. To prepare a two-molar buffer, two-molar citric acid was added to two-molar sodium citrate solution to produce the desired hydrogen ion concentration. In carrying out each of the examples a developing eluant was used, as explained in detail in connection with the first example.

The organic solvent mixed with the adsorbent in forming the bed is first allowed to drain until there is no excess solvent standing on the top of the bed. The solution of the mixture of dicarboxylic acids was then added to the top of the column and allowed to drain until only a few drops of excess solvent remained at the head of the adsorbent section. A developing eluant was employed in which each succeeding increment contained an increasing amount of n-butanol, as explained in connection with the first example. One milliliter of the initial developing eluant was used to wash down the side of the column and this was again allowed to drain until nearly gone. This last washing process was repeated twice more before filling the column with the remainder of the developing eluant.

A total of 400 milliliters of doveloping eluant was employed with each example. The elnate was collected as forty l-milliliter samples each of which was titrated to determine the amount of the dicarboxylic acid present. The amount present in each sample was plotted to give the curves shown in Figs. 2 through 4. In order to illustrate the separation of monocarboxylic acids from the dicarboxylic acids, a certain amount of benzoic acid was added to each sample of mixed dicarboxylic acids. The nature of the monocarboxylic acid present as impurity will vary with the process employed in producing the dicarboxylic acids. The process here disclosed may be grams of silicic acid (chromatographic used for separating from the dicarboxylic acids such less polar monocarboxylic acids as pelargonic acid, caproic acid, capric acid, caprylic acid, and other higher molecular weight straight chain aliphatic monocarboxylic acids.

Example 1 A one-per cent solution of a mixture of 10.0 mg. each of sabacic, azelaic, suberic and pimelic acids was prepared in a mixed solvent of 5 per cent t-amyl alcohol and per cent chloroform. (All percentage mixtures of solvents mentioned herein refer to percentage by volume.) The solution is advantageously prepared by dissolving the acids in the warm amyl alcohol and then adding the chloroform.

A 5 ml. sample of the solution is pipetted into the apparatus prepared with one molar citrate buffer with a pH of 5.40.

After the solution of the mixed acids had been allowed to drain through the bed, it was developed with eluant to recover the respective acids. Four hundred milliliters of eluant were used, succeeding increments being more and more polar, as follows:

Volume of n-Butanol Volume of Ten milliliter fractions of eluate were collected. These were analyzed by the following procedure: Five milliliters of absolute alcohol are added to each fraction. The fractions were then titrated with 0.04 to 0.05 N alcoholic sodium hydroxide. Meta cresol purple was used as an indicator. The alcohol was added to sharpen the endpoint and to permit single-phase titration of the chloroform solutions. The respective fractions were analyzed for their acid content, and the curve shown in Fig. 2 was obtained by plotting the acid present in each of the forty 10 ml. samples of eluate in the order in which they were obtained. The sample contained adipic acid which was not eluted, but remained in the bed. The higher molecular weight monobasic acids are less polar than the dicarboxylic acids and would be eluted before the dicarboxylic acids as benzoic acid was in the example.

For separation of the acids in their pure form on a commercial scale it is not necessary to collect the eluate in increments of the same sizeassuming of course that the mixture of acids treated remains substantially constant in composition. After it has been determined where the peaks are, and in general where the fractions are to be collected in order to recover all or substantially all of the respective acids in individual fractions, it can be determined what fractions will be collected, assuming there is only small variance in the analysis of the starting mixture. However, a continuous check of the acidity of the eluate will ordinarily be preferable, the acid portions of elnate being separately collected and containing the respective dicarboxylic acids. Electronic means may be employed for determining the onset of the respective elution peaks and the collection of the fractions be controlled accordingly, to collect the respective acids with minimum solute-free elnate. This will permit the separate recovery of solutefree elnate forreuse with adjustment of polarity as required.

Thus, referring to Fig. 2, the first 60 ml. will be separately collected to remove the monobasic acid impurity. The next five or six fractions or possibly the next 5.5 (which will be larger than indicated on the graph if the operation is carried out on a commercial scale) will be separately recovered and treated for the separation of sebacic acid. Fractions 14 to 18 will be collected toof the acids from one another.

*27 'will alsofb'e' included. The 'intermediate fractions of eluate, which "contain 'no'acid or only "an inapp'reciable amount, will be reused as solvent or eluant .with'adjust- 'r'nento'fthepolarity as required. 'Thus thev'arious acids are separated and recovered, in any suitable manner fas 'by'remova l' of 'th'esolvent by"distillation.

uExampl'e H fln'th'isexample, a-one molar citrate buffer ofpH 5.20

wasfused. .The samemixture of .dicar'boxylic acids was addedlin amylalcohol-chloroiorm solution, as before. The respective acids were recovered'in different fractions of the eluate as shown by the curve in Fig.3.

The results illustrate the eifectof'hydrogen ion concen tration on the elution rate and position of the peaks in the curve. The shift to the left shows an increase in the elution rate. IA .low'erpHwouldcause-anygiven acid component toielute'earlier andpossible elutioniof a lower molecular weight acidbefore .all of the highermolecular'weig'ht a'cidhas be'en eluted from the system. The curve illustrates the impossibility of entirely separating a monobasic acid such as benz'oic acidfromthe C10 dicarboxylic acid. *I-Iowever, u'singthis-pH the respective '-dicarboxy'lic acids including adipic acid can be F separated from one another.

Example III 111 this examp'1e,'two molar'citr'ate buffer of pH 5.40 was used. to ,prepare the column. Although the pH is the same a'sWiththe'firs't example the "curve(Fig. 4') shows a slight increase in the rate of .elution, possibly due to "the saltingout eiiect of' the higher concentratlonof salt in the aqueous phase. As a result the separation between sebacic acid and the monobasic acid is not complete.

The process may be used for the separation of several It may likewise be used to separate an impurity from one or more ofthe acids. It may be used to separate only two acids. Likewise it may be used to separate one or more acids of higher molecular weight from one of more acids of lower molecular weight. In a continuous process the feed will be introduced at an intermediate point in the system, more polar of the feed materials will be removed with the adsorbent and the less polar with the eluate.

What I claim is:

l. The process of separating two adjacent homologues of the straight-chain alpha, omega-dicarboxylic acids containing six to ten carbon atoms in a two-phase system which includes an aqueous liquid phase and an organic liquid phase, utilizing the partition coefiicients of the respective acids, said partition coefficients being different, which process comprises preparing a bed of hydrophilic adsorbent wet with aqueous butler which is soluble in the aqueous phase and substantially insoluble in the organic phase and has a strength no greater than three molar and a pH of 5.1 to 6.0, and providing organic phase in the bed, introducing into the bed a solution of a mixture of the acids in solvent which eventually forms part of the organic phase eluate, and while the aqueous phase adheres to the bed, washing the bed with organic eluant immiscible with the aqueous phase and which eventually forms organic phase eluate, thereby dissolving into the aqueous phase the shorter chain dicarboxylic acid and retaining it there while removing the longer chain dicarboxylic acid from the system dissolved in the organic phase eluate, and maintaining the organic phase in moving contact with the aqueous phase during the washing for a sufiicient period to effect substantially complete separation of the two acids.

2. The process of separating adipic acid, pimelic acid, suberic acid, azelaic acid and sebacic acid from an admixture thereof utilizing a two-phase separation system which includes an aqueous liquid phase and an organic liquid phase immiscible with one another, utilizing thelpartition edetfieients of the respective acids, which process com- .pri'ses preparing a bed-of hydrophilic'adsorbent wet with aqueous-butter which'issoluble in the aqueous phase and substantially insolubledn theforganic phase and has a 's'trengthjno greater than three molar and a pH of 5.1 to 6.O atidprbviding liquid organic phase in the bed, introdiicirig into the bed asolution of a mixture of the acids insolvent which eventually forms part of the organic phaseeluat'e, 'and while the aqueous phaseadheres to the bed washing the bed with organic eluant immiscible with the aqueous phasewhich'eluarit eventually forms organic phase eluate, thereby dissolving the adipic, pimelic,*suber'ic ari'daz'elaic acids into the aqueous phase while removing the sebacic aeid from the system in the organic phase eluate, and thensuccessivelydissolving the azelaic acid, the suberic'acid,'the'piinelic acid and-the adipic acid into the-organic phase while maintaining the organic phase in moving contact with the aqueous phase and removing the acids fromthe system-as eluate,' and separately collecting the portions "of'eluate containing the respective acids.

3. The'process of separating suberic acid, azelaic acid andseba'cic 'a'eid'frotn an admixture thereof utilizing a two- -ph'ase separation system which'includes an aqueous liquid phase and an organic liquid phase immiscible with one another, utilizing the partition coefficients of'the respective acids, which process comprises preparing a'bed of hydrophilic adsorbent 'wetwith'aqueous buffer which is soluble inthe aqueous phase and substantially insoluble in the erganic phase and has-a strength no greater than three molar and-apHef 5. 1 to 6.0, andprovidingliquidorganic phase in the bed, introducing into the bed a solution of a mixtu-reof said acids in solvent which eventually forms part of the organic phase eluant, and while the aqueous .phase adheres to the =bed'washing the bed with organic eluant immiscible with the aqueous phase which eluant eventually forms organic phase eluate, thereby dissolving the suberic and azelaic acids into the aqueous phase while removing the sebacic acid from the system in the organic phase eluate, and then successively dissolving the azelaic acid and the suberic acid into the organic phase while maintaining the organic phase in moving contact with the aqueous phase and removing these acids from the system as eluate, and separately collecting the portions of eluate containing the respective acids.

4. The process of separating pimelic acid, suberic acid and azelaic acid from an admixture thereof utilizing a two-phase separation system which includes an aqueous liquid phase and an organic liquid phase immiscible with one another, utilizing the partition coefficients of the respective acids, which process comprises preparing a bed of hydrophilic adsorbent wet with aqueous buffer which is soluble in the aqueous phase and substantially insoluble in the organic phase and has a strength no greater than three molar and a pH of 5.1 to 6.0, and providing liquid organic phase in the bed, introducing into the bed a solution of a mixture of said acids in solvent which eventually forms part of the organic phase eluant, and while the aqueous phase adheres to the bed Washing the bed with organic eluant immiscible with the aqueous phase which eluant eventually forms organic phase eluate, thereby dissolving the pimelic and suberic acids into the aqueous phase while removing the azelaic acid from the system in the organic phase eluate, and successively dissolving the suberic acid and the pimelic acid into the organic phase while maintaining the organic phase in moving contact with the aqueous phase and removing these acids from the system as eluate, and separately collecting the portions of eluate containing the respective acids.

5. The process of separating suberic acid and azelaic acid from an admixture thereof utilizing a two-phase separation system which includes an aqueous liquid phase and an organic liquid phase immiscible with one another, utilizing the partition coefficients of the respective acids, which process comprises preparing a bed of hydrophilic adsorbent wet with aqueousbufier which is soluble in the aqueous phase and substantially insoluble in the organic phase and has a strength no greater than three molar and a pH of 5.1 to 6.0, and providing liquid organic phase in the bed, introducing into the bed a solution of a mixture of said acids in solvent which eventually forms part of the organic phase eluant, and while the aqueous phase adheres to the bed washing the bed with organic eluant immiscible with the aqueous phase which eluant eventually forms organic phase eluate, thereby dissolving the suberic acid into the aqueous phase while removing the azelaic acid from the system in the organic phase eluate.

6. The process of separating azelaic acid and sebacic acid from an admixture thereof utilizing a two-phase separation system which includes an aqueous liquid phase and an organic liquid phase immiscible with one another, utilizing the partition coefficients of the respective acids, which process comprises preparing a bed of hydrophilic adsorbent wet with aqueous buffer which is soluble in the aqueous phase and substantially insoluble in the organic phase and has a strength no greater than three molar and a pH of 5.1 to 6.0, and providing liquid organic phase in the bed, introducing into the bed a solution of a mixture of said acids in solvent which eventually forms part of the organic phase eluant, and while the aqueous phase adheres to the bed washing the bed with organic eluant immiscible with the aqueous phase which eluant eventually forms organic phase eluate, thereby dissolving the azelaic acid into the aqueous phase while removing the sebacic acid from the system in the organic phase eluate.

7. The improvement in the process of chromatographically separating two adjacent homologues of the straight-chain alpha, omega-dicarboxylic acids containing 8 six to ten carbon atoms, employing an absorbent bed and a two-phase liquid system, using water as the internal phase and an immiscible solvent as the external phase, which improvement comprises using an acid bufier with a pH above 4.5 in the aqueous internal phase and using water-immiscible organic eluant to dissolve the acids successively.

References Cited in the file of this patent UNITED STATES PATENTS 2,170,601 Wilson et al. Aug. 22, 1939 2,296,850 Harrison Sept. 29, 1942 2,352,932 Barrett et al. July 4, 1944 2,470,339 Claussen et a1 May 17, 1949 FOREIGN PATENTS 558,320 Great Britain Dec. 31, 1943 585,224 Great Britain Feb. 3, 1947 OTHER REFERENCES Blackburn: Biochemical Journal, vol. 45, 1949, pages 579-84.

Marvel et al.: J. Am. Chem. Soc., vol. 72, pages 2642-6, 1950.

Dobson et al.: ibid., page i of Proceedings. 

1. THE PROCESS OF SEPARATING TWO ADJACENT HOMOLOGUES OF THE STRAIGHT-CHAIN ALPHA, OMEGA-DICARBOXYLIC ACIDS CONTAINING SIX TO TEN CARBON ATOMS IN A TWO-PHASE SYSTEM WHICH INCLUDES AN AQUEOUS LIQUID PHASE AND AN ORGANIC LIQUID PHASE, UTILIZING THE PARTITION COEFFICIENTS OF THE RESPECTIVE ACIDS, SAID PARTITION COEFFICIENTS BEING DIFFERENT, WHICH PROCESS COMPRISE PREPARING A BED OF HYDROPHILIC ADSORBENT WET WITH AQUEOUS BUFFER WHICH IS SOLYBLE IN THE AQUEOUS PHASE AND SUBSTANTIALLY INSOLUBLE IN THE ORGANIC PHASE AND HAS A STRENGTH NO GREATER THAN THREE MOLAR AND A PH OF 5.1 TO 6.0, AND PROVIDING ORGANIC PHASE IN THE BED, INTRODUCING INTO THE BED A SOLUTION OF A MIXTURE OF THE ACIDS IN SOLVENT WHICH EVENTUALLY FORMS PART OF THE ORGANIC PHASE CLUATE, AND WHILE THE AQUEOUS PHASE ADHERES TO THE BED, WASHING THE BED WITH ORGANIC ELUANT IMMISCRIBLE WITH THE AQUEOUS PHASE AND WHICH EVENTUALLY FORMS ORGANIC PHASE ELUATE, THEREBY DISSOLVING INTO THE AQUEOUS PHASE 